1. Introduction
This invention relates to derivatives of penicillin and more particularly to carbon and oxygen analogs of 6-aminopenicillanic acid and biologically active derivatives thereof.
2. Description of the Prior Art
In U.S. Pat. No. 3,159,617, there is taught the first commercial synthesis 6-aminopenicillanic acid and penicillin derivatives based thereon. A vast number of derivatives of the 6-aminopenicillanic acid may be formed by introduction of various groups into the amino group of the acid. Thus, acyl groups, isocyanates, isothiocyanates, halogen compounds, methylisoureas, ethylene oxide, ethylene imine, and the like have been introduced into the amino group of the 6-aminopenicillanic acid to form both biologically active and biologically inactive derivatives.
Many of the derivatives of 6-aminopenicillanic acid, especially those derivatives formed by acylation have become useful drugs. For example, ampicillin and carbenicillin have broadened the spectra of activity to include use against certain Gram-negative organisms while methicillin shows good activity against certain resistant staphylococci.
In an effort to find new biologically active derivatives of 6-aminopenicillanic acid, attempts have been made to modify the same by methods in addition to introduction of new groups into the amino group. Thus, stimulated by the elucidation of the structure of the cephalosporins, there have been attempted modifications of the thiazolidine moiety of 6-aminopenicillanic acid. This is especially true since cephalosporins are not readily available from nature and most of the drugs used today are converted from penicillins. Thus, much effort has been concentrated on the investigation of possible transformation of the thiazolidine ring to the dihydrothiazine ring without any concomitant change of the chemically sensitive .beta.-lactam moiety. These efforts are described by D. H. R. Barton and T. G. Sammes, Proc. R. Soc. Lond. D, 179 345 (1971).
Other attempts have been made to modify 6-aminopenicillanic acid through modification of the .beta.-lactam moiety, but such attempts are relatively few and are focused on the variations on the substituents or stereochemistry of the C-6 carbon in the penam system. Primarily, four types of modifying reactions are reported, namely acylation, epimerization, alkylation and diazotization.
One successful example of the epimerization reaction is reported by G. E. Gutowski, Tet Lett., 1970, 1779 and 1863. However, this penicillin having the epimerized C-6 substituent is devoid of any biological activity. With regard to alkylation at the C-6 position, most attempts have been to introduce an .alpha.-alkyl group based upon earlier predictions that the introduction of an .alpha.-methyl group at the C-6 position might enhance antibiotic activity. Both direct and indirect .alpha.-hydroxyalkylation of the penicillin nucleus at C-6 with benzldehyde and formaldehyde is reported by R. Riner and P. Zeller, Helv Chim. Acta 51, 1905 (1968). These derivatives and other .alpha.-alkylated derivatives show some biological activity, but both show substantially less activity than the well known penicillin G. Deamination of 6-aminopenicillanic acid by sodium nitrite in mineral acid proceeds with the inversion at C-6 resulting in the C-5 and C-6 protons being trans-oriented in the product. When the reaction is run in the presence of a halo acid, a 6-.alpha.-halo product is obtained. Deamination of 6-aminopenicillanic acid by sodium nitrite with oxygen acids is reported by T. Hauser and H. P. Sigg, Helv, Chim, Acta, 50, 1327 (1967). With such oxygen acids, 6.alpha.-hydroxypenicillanic acid is isolated as the benzyl ester which may then be transformed to the .alpha.-oxygen analog 6-.alpha.-phenoxyacetoxypenicillanic acid, the .alpha.-oxygen analog of penicillin V. This material shows no biological activity.